Antibiotics versus placebo or watchful waiting for acute otitis

media: a meta-analysis of randomized controlled trials

Evridiki K. Vouloumanou
1
, Drosos E. Karageorgopoulos
1
, Maria S. Kazantzi
1
, Anastasios
M. Kapaskelis
1,2
and Matthew E. Falagas
13
*
1
Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece;
2
Department of Medicine, Henry Dunant Hospital,
Athens, Greece;
3
Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
Received 16 December 2008; returned 9 February 2009; revised 2 April 2009; accepted 13 April 2009
Background: Recommendations on withholding antibiotics in children with acute otitis media (AOM)
have been inadequately implemented in clinical practice.
Objectives: We evaluated the role of prescribing antibiotics for AOM.
Methods: We performed a meta-analysis of randomized controlled trials (RCTs) that were retrieved
from searches performed in the PubMed and Cochrane databases, and compared antibiotic treatment
with placebo or watchful waiting (delayed antibiotic treatment if clinically indicated) for patients
with AOM.
Results: We identied seven trials comparing antibiotic treatment with placebo (all double-blinded)
and four trials comparing antibiotic treatment with watchful waiting (two investigator-blinded and two
open-label) trials, all of which involved children (6 months to 12 years). Clinical success was more
likely with antibiotics than comparator treatment in: placebo-controlled trials [seven RCTs, 1405
patients, risk ratio (RR)51.11, 95% condence interval (CI)51.051.18]; watchful waiting trials (four
RCTs, 915 patients, RR51.18, 95% CI 51.071.32); and all trials combined (11 RCTs, 2320 patients,
RR51.13, 95% CI 51.081.19). Similarly, persistence of symptoms 24 days after treatment initiation
was less likely with antibiotics in: placebo-controlled trials (four RCTs, 1014 patients, RR50.75, 95%
CI 50.640.88) and all trials combined (ve RCTs, 1299 patients, RR50.68, 95% CI 50.540.85).
Diarrhoea was more likely with antibiotics (seven RCTs, 1807 patients, RR51.50, 95% CI 51.161.95).
No differences between the compared treatments were found regarding other effectiveness and safety
outcomes.
Conclusions: Antibiotic treatment is associated with a more favourable clinical course in children with
AOM, compared with placebo, and also compared with watchful waiting. However, safety issues and
the rather small treatment effect difference render the consideration of additional factors necessary in
relevant clinical decision making.
Keywords: upper respiratory tract infections, drug therapy, ear diseases, treatment outcome, delayed antibiotic
treatment, wait-and-see strategy
Introduction
Acute otitis media (AOM) is a common community-acquired
infection, particularly in young children. AOM is primarily
caused by bacteria, such as Streptococcus pneumoniae, non-
typeable Haemophilus inuenzae and Moraxella catarrhalis; res-
piratory viruses may also play a role as co-pathogens.
13
The clinical decision to treat or not to treat children with
AOM with antibiotics is not always a clear-cut one.
4
According
to current relevant US guidelines, factors that should be taken
into consideration in this clinical decision include age, the
degree of certainty about the diagnosis and the severity of
illness.
5
For a considerable proportion of patients, antibiotic
therapy may be initially withheld and instituted later in case the
child fails to improve within 4872 h.
5
Additionally, relevant
UK guidance suggests that immediate antibiotic therapy should
be considered for children younger than 2 years with bilateral
AOM or for children presenting with otorrhoea. For all other
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoles Street, 15123 Marousi, Athens, Greece.
Tel: 30-694-61-10-000; Fax: 30-210-68-39-605; E-mail: m.falagas@aibs.gr
Journal of Antimicrobial Chemotherapy (2009) 64, 1624
doi:10.1093/jac/dkp166
Advance Access publication 19 May 2009
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
# The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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patients with AOM, a no antibiotic or delayed antibiotic pre-
scribing strategy is recommended.
6
The implementation of the
above-mentioned guidelines appears to have contributed to the
observed decrease in the antibiotic prescriptions for children
with AOM.
79
In this regard, we aimed to re-evaluate the effectiveness and
safety of antibiotic treatment for AOM compared with placebo and
particularly with watchful waiting, by performing a comprehensive
meta-analysis of relevant randomized controlled trials (RCTs).
Methods
Data sources
The clinical trials to be included in our meta-analysis were retrieved
from searches performed in PubMed and the Cochrane Library (up to
31 March 2009 for both databases), as well as by hand-searching the
bibliographies of relevant articles. The PubMed search strategy was:
otitis AND (antibiotic OR antibiotics OR drug OR antimicrobial
agents) AND (therapy OR treatment). The search criteria applied to
the Cochrane Library were: otitis AND (antibiotics OR placebo).
Study selection process
Two reviewers independently performed the literature search as well
as the evaluation of retrieved articles. The latter were initially
screened on the basis of title or abstract. Full text was obtained for
the articles that were selected for further evaluation. A study was
included in the meta-analysis if it constituted an RCT; evaluated
patients of any age diagnosed with AOM; compared treatment with
antibiotics versus either placebo or a watchful waiting strategy; and
provided data relevant to the effectiveness or safety outcomes of
this meta-analysis. We considered as watchful waiting a strategy of
reserving antibiotic treatment for patients not showing an adequate
clinical response. Trials that included patients with mixed types of
upper respiratory tract illnesses were included in the meta-analysis if
.75% of the patients had symptoms and signs of AOM. The latter
consisted of a history of acute onset, along with symptoms and
signs of middle ear inammation and signs of middle ear effusion.
5
Articles representing abstracts in scientic conferences or published
in languages other than English, Spanish, French, German or Italian
were excluded from the meta-analysis.
Data extraction
Data extracted from each of the included RCTs consisted of study
design and methodology, characteristics and size of the included
population, criteria used for AOM diagnosis along with exclusion
criteria, characteristics of compared treatments and potential conco-
mitant therapies, as well as specic data regarding the outcomes
evaluated in this meta-analysis and the timing of relevant
evaluations.
Outcomes of the meta-analysis
The primary effectiveness outcome of the meta-analysis was clinical
success, dened as cure or improvement (complete or substantial
resolution, respectively) of all symptoms and signs of AOM. For
trials that only reported relevant data regarding specic symptoms
or signs, we elected pain as a surrogate marker for clinical
success.
10
If data on the resolution of symptoms or signs were
not reported, we dened clinical success as the absence of an
unfavourable clinical course. The timing of determination of clinical
success was during the course of therapy or a few days thereafter.
The secondary effectiveness outcomes of our meta-analysis
included: cure, determined at the rst post-treatment evaluation;
short-term persistence of symptoms, dened as the presence of any
AOM-related symptoms (or specically pain if only data on specic
symptoms were reported) within 24 days after the initiation of study
treatments (we included data obtained at the earliest relevant assess-
ment); bacteriological success, dened as the eradication of the
initially isolated pathogens at the post-treatment evaluation; disease
complications, which included eardrum perforation, as well as pro-
gression to severity requiring hospitalization, and intracranial or
extracranial suppurative complications, and were determined during
or shortly after treatment; development of persistent middle ear effu-
sion, determined at the last follow-up assessment; and recurrence of
AOM, dened as the reappearance of symptoms and signs of the
disease in patients previously evaluated as cured, and determined at
the last follow-up assessment. The safety outcomes of the
meta-analysis consisted of adverse events, dened as total adverse
events reported during the study period; along with specic common
types of adverse events; and study withdrawals due to adverse events.
The effectiveness outcomes of the meta-analysis were assessed
on the respective evaluable population, which included patients who
satised the criteria for eligibility of evaluation for a specic
outcome that were set in each RCT. If the number of the latter was
not specied, we used the intention-to-treat patients (all patients
randomized to receive study treatments) as the denominator. Only
patient-related data, as opposed to data related to infected ears, were
entered in the meta-analysis.
Subgroup and sensitivity analysis
The main analysis consisted of the separate evaluation of trials com-
paring antibiotic treatment with placebo and those comparing anti-
biotic treatment with watchful waiting. In a complementary analysis,
we also evaluated all trials combined. In a sensitivity analysis, we
evaluated clinical success in trials that used rigorous criteria for the
diagnosis of AOM (specied as history of acute onset, along with
the presence of symptoms and signs of middle ear inammation,
and signs of middle ear effusion),
5
as well as in the remaining trials,
and we tested for difference between the above subgroups of trials.
Quality assessment
The methodological quality of each of the included RCTs was
assessed by the Jadad criteria. The Jadad criteria evaluate the pres-
ence of randomization, blinded design and information on study
withdrawals, as well as the appropriateness of randomization and
blinding procedures, if present. Specically, one point is awarded
for the presence of each of the former three parameters, whereas
each of the latter two parameters is awarded the values of 21 (if
deemed inappropriate) and 1 (if appropriate). In this regard, the
maximum score that could be attributed to any specic trial was 5
points. A score higher than 2 points denoted adequate methodologi-
cal quality.
11,12
Statistical analysis
For outcomes expressed as dichotomous variables, pooled risk ratios
(RRs) and respective 95% condence intervals (CIs) regarding the
analysed outcomes were estimated using a random effects model.
Statistical heterogeneity among trials was assessed by the I
2
-test; a
value of 25%, 50% and 75% for the I
2
-test was considered to
Systematic review
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correspond to statistical heterogeneity of a low, moderate and high
degree, respectively.
13
All statistical analyses were performed with
the Review Manager (RevMan) v.5.0 Software (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2008).
Results
Selected RCTs
The ow diagram of the selection process of eligible articles
for inclusion in the meta-analysis is presented in Figure S1
[available as Supplementary data at JAC Online (http://
jac.oxfordjournals.org/)]. Briey, among a total of 7418 and 736
articles initially retrieved from the PubMed and the Cochrane
Library searches, respectively, we nally selected 11 individual
RCTs as eligible for inclusion in the meta-analysis.
1424
Characteristics of the included RCTs
The main characteristics of the 11 RCTs included in the meta-
analysis are presented in Table S1 [available as Supplementary
data at JAC Online (http://jac.oxfordjournals.org/)]. All of the
included RCTs involved children, whose age varied from 6 months
to 12 years. Among the 11 RCTs, 7 compared antibiotic treatment
with placebo,
1420
whereas the remaining 4 compared antibiotic
treatment with a watchful waiting strategy (delayed antibiotic
treatment for patients when this was clinically indicated).
2124
Regarding trials of the latter type, in two the decision to administer
antibiotics was regulated by the study investigators, whereas, in the
remaining two, antibiotic prescriptions were issued for all patients
but the patients parents were instructed on whether and when to
use them.
21,23
All the included placebo-controlled RCTs had a
double-blinded design.
1420
Regarding the four RCTs comparing
antibiotic treatment with watchful waiting, two had a single-
(investigator-) blinded design,
21,22
one had an open-label design
23
and the remaining trial did not report about blinding.
24
Regarding
methodological quality, all of the included RCTs were assigned a
Jadad score of .2 points, with the exception of one RCT that had
a Jadad score of 2 points.
24
Characteristics of treatment administered
Regarding the RCTs that used placebo as the comparator treat-
ment, four of the seven used amoxicillin in the antibiotic treat-
ment arm,
14,15,17,19
while amoxicillin/clavulanate
16
and penicillin
V
18
were used in one RCT each, and the remaining RCT had
two antibiotic treatment arms, involving amoxicillin or phenoxy-
methyl penicillin combined with sulsoxazole.
20
Regarding the RCTs that used a watchful waiting strategy as
the comparator treatment, two of the four RCTs used amoxicillin
in the immediate antibiotic treatment arm,
22,23
another one used
penicillin and amoxicillin in two respective antibiotic treatment
arms,
24
whereas, in the remaining relevant trial, the choice of
antibiotics administered was left at the discretion of the clini-
cians participating in the study.
21
In three of the four above-
mentioned trials,
2123
the antibiotics used in the watchful
waiting treatment arms were the same as those used in the
immediate antibiotic treatment arms, while in the remaining trial
relevant data were not specically reported.
24
The watchful
waiting strategy used in these trials consisted of the institution
of antibiotic treatment in the event of persistence or recurrence
of the clinical manifestations of AOM. However, the exact meth-
odology used was variable.
Among the 11 included RCTs, the duration of antibiotic
therapy was 7 days in four trials,
1619
10 days in ve
trials,
14,15,2022
while in one trial antibiotics were administered
for a variable duration of between 7 and 14 days (average
10 days).
24
Specic data regarding this outcome were not pro-
vided for the remaining RCT.
23
In all of the included RCTs,
patients received concomitant symptomatic therapy, such as
analgesics or decongestants.
Outcomes of the meta-analysis
In Table S2 [available as Supplementary data at JAC Online
(http://jac.oxfordjournals.org/)], we present the data extracted
from each of the included RCTs that were taken into consider-
ation for the analyses of the outcomes we performed. The
respective ndings are presented below.
Effectiveness outcomes. Clinical success was more likely in
patients treated with antibiotics versus comparator treatment in
the subgroup analysis limited to placebo-controlled trials,
1420
in the subgroup analysis limited to watchful waiting trials
2124
and in the combined analysis including all trials.
1424
The
specic relevant outcome data are shown in Figure 1. In the sen-
sitivity analysis, no difference regarding clinical success was
noted between the trials that used rigorous diagnostic inclusion
criteria and the remaining trials (ve RCTs, 1503 patients,
RR1.14, 95% CI1.091.20,
14,15,2123
versus six RCTs, 817
patients, RR1.12, 95% CI 1.061.18,
1620,24
respectively;
P0.61 for the x
2
test for subgroup differences). It should be
mentioned that for two of the included trials we used resolution
of pain as a surrogate marker of clinical success, as specic data
for the latter outcome were not reported. These two trials, one of
which compared antibiotics with placebo
19
and the other with
watchful waiting,
21
did not show signicant difference in the
resolution of pain between the compared treatment arms.
No difference was found regarding cure between patients
treated with antibiotics and those treated with comparator treat-
ment in the subgroup analysis limited to placebo-controlled
trials (two RCTs, 306 patients, RR1.05, 95% CI0.61
1.82)
15,20
as well as in the combined analysis including all trials
(three RCTs, 448 patients, RR1.15, 95% CI0.71
1.85).
15,20,24
Specic data regarding this outcome were reported
in one of the four included watchful waiting trials.
24
Short-term persistence of symptoms was less likely in patients
treated with antibiotics versus comparator treatment in the
subgroup analysis limited to placebo-controlled trials
1416,18
and
in the combined analysis including all trials.
1416,18,23
Specic
data regarding this outcome were reported in one of the four
included watchful waiting trials.
23
The specic relevant outcome
data are shown in Figure 2.
No difference was found regarding eardrum perforations
between patients treated with antibiotics and those treated with
placebo (two RCTs, 381 patients, RR0.57, 95% CI0.25
1.33).
17,18
Relevant data were not reported in the included
watchful waiting trials. No difference was also found regarding
hospitalizations between patients treated with antibiotics and those
treated with comparator treatment in the combined analysis
including all trials (two RCTs, 463 patients, RR0.36, 95%
Systematic review
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CI0.062.36).
15,22
Specic data regarding this outcome were
reported in one placebo-controlled
15
and one watchful waiting
trial.
22
No difference was found regarding the development of
middle ear effusion between patients treated with antibiotics and
those treated with placebo (three RCTs, 872 patients, RR0.95,
95% CI0.741.20).
14,15,17
Specic data regarding this
outcome were not provided from the included watchful waiting
trials. No difference was found regarding recurrences between
patients treated with antibiotics and those treated with compara-
tor treatment in the subgroup analysis limited to watchful
waiting trials (two RCTs, 351 patients, RR1.32, 95%
CI 0.832.08)
22,24
or in the combined analysis including all
trials (three RCTs, 822 patients, RR1.07, 95% CI 0.80
1.42).
14,22,24
Specic data regarding this outcome were reported
in one of the seven included placebo-controlled trials.
14
Safety outcomes. No difference was found regarding the occur-
rence of diarrhoea between patients treated with antibiotics and
those treated with placebo.
14,15,17,18
Diarrhoea was more likely
in patients treated with immediate antibiotics versus those
treated with a watchful waiting strategy.
21,23,24
Overall, diarrhoea
was more likely in patients treated with antibiotics versus com-
parator treatments in the combined analysis including all trials,
both placebo-controlled and watchful waiting.
14,15,17,18,21,23,24
The specic relevant outcome data are shown in Figure 3.
No difference was found regarding the occurrence of rash
between patients treated with antibiotics and those treated with
comparator treatment in the subgroup analysis limited to
placebo-controlled trials,
14,15,17,18
in the subgroup analysis
limited to watchful waiting trials
23,24
and in the combined analy-
sis including all trials.
14,15,17,18,23,24
The specic relevant
outcome data are shown in Figure 4.
No difference was found regarding study withdrawals
between patients treated with antibiotics and those treated with
comparator treatment in the subgroup analysis limited to
placebo-controlled trials (ve RCTs, 1259 patients, RR1.24,
95% CI0.344.56)
1418
or in the combined analysis including
all trials (eight RCTs, 1939 patients, RR1.24, 95% CI 0.34
4.56).
1418,2224
No study withdrawals were reported in three of
the four included watchful waiting trials.
2224
Discussion
The main nding of our meta-analysis is that clinical success in
children with AOM, during or shortly after treatment, is more
likely to be noted in those treated with antibiotics compared
Figure 1. Clinical success (cure or improvement) in children with AOM who were treated with antibiotics compared with either placebo or according to a
watchful waiting strategy. The vertical line indicates no difference between the compared treatment groups. RRs (95% CI) are shown by diamond shapes;
95% CIs are shown by horizontal lines. Squares indicate point estimates; the size of the squares indicates the weight that each individual study has in the
meta-analysis. M-H, Mantel Haenszel random effects model.
Systematic review
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with those treated with placebo. Moreover, antibiotic treatment
is associated with a lower likelihood of persistence of
AOM-related symptoms within 24 days after the initiation of
treatment. However, diarrhoea was more frequently observed in
the antibiotic group. No difference between the compared
groups was found in the remaining comparisons performed.
The clinical signicance of the above ndings merits further
interpretation. The margin of benet of antibiotics over placebo
in achieving a favourable clinical course does not appear to be
large. Whether such an effect size can justify a universal policy
in favour of or against prescribing antibiotics for children with
AOM is a multifaceted issue.
The rapidity of resolution of symptoms is an important
quality of life outcome measure for diseases that tend to have a
self-limiting nature, such as AOM. Continuing AOM-related
symptoms, such as pain, fever and irritability, are also a source
of parents anxiety and distress.
25,26
Moreover, parents may need
to take time off work to provide special care for the sick
child.
27,28
For older children, prolongation of the course of AOM
may relate to increased number of days lost from school.
17,28
In
our meta-analysis, antibiotics were superior to placebo with
regard to short-term resolution of symptoms, so they may have a
value in improving the quality of life of patients or caregivers. A
study that used a decision analysis approach to assess the above-
mentioned issues and, additionally, economic costs, estimated
that deferring antibiotic therapy for children meeting the current
US guidelines criteria would result in 0.34 lost quality of
life-adjusted days.
29
The above benecial effects of antibiotics in terms of clinical
effectiveness, translated into improved quality of life, may be
counterbalanced by the development of treatment-related
adverse events. Specically, diarrhoea was found to be more
likely in patients treated with antibiotics compared with those
who were not initially treated with antibiotics. Similar ndings
have also been shown for acute sinusitis, which shares many fea-
tures with AOM.
30
Another consideration regarding the value of antibiotics for
AOM is their role in preventing disease complications. Although
severe complications of AOM, such as mastoiditis and meningi-
tis, are still being observed at a low, albeit not negligible, rate
in community cases,
3133
they were rarely observed in our
meta-analysis. Moreover, the incidence of acute mastoiditis
appears to be higher in countries that have followed a restrictive
antibiotic prescribing policy for AOM, compared with countries
with high relevant antibiotic prescription rates.
34
An important question regarding the treatment of AOM is
whether a strategy of reserving antibiotics for the children who
appear to be in need for such treatment after a relatively short
watchful waiting period is equally effective as a strategy of
immediate institution of antibiotics to all candidate patients. In
our meta-analysis, the difference in clinical effectiveness
between a strategy of early administration of antibiotics versus a
watchful waiting strategy did not appear smaller than that
observed in trials comparing antibiotics with placebo. The above
observation may indicate that the benet of antibiotics in improv-
ing the outcome of AOM is greater if they are administered early
Figure 2. Short-term persistence of symptoms in children with AOM who were treated with antibiotics compared with either placebo or according to a
watchful waiting strategy. The vertical line indicates no difference between the compared treatment groups. RRs (95% CI) are shown by diamond shapes;
95% CIs are shown by horizontal lines. Squares indicate point estimates; the size of the squares indicates the weight that each individual study has in the
meta-analysis. M-H, Mantel Haenszel random effects model.
Systematic review
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Figure 3. Diarrhoea in children with AOM who were treated with antibiotics compared with either placebo or according to a watchful waiting strategy. The vertical
line indicates no difference between the compared treatment groups. RRs (95% CI) are shown by diamond shapes; 95% CIs are shown by horizontal lines. Squares
indicate point estimates; the size of the squares indicates the weight that each individual study has in the meta-analysis. M-H, MantelHaenszel random effects model.
Figure 4. Rash in children with AOM who were treated with antibiotics compared with either placebo or according to a watchful waiting strategy. The
vertical line indicates no difference between the compared treatment groups. RRs (95% CI) are shown by diamond shapes; 95% CIs are shown by horizontal
lines. Squares indicate point estimates; the size of the squares indicates the weight that each individual study has in the meta-analysis. M-H, Mantel Haenszel
random effects model.
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in the course of the infection, when the host defence responses
have not been fully activated.
35
Notably, early administration of
antibiotics has been associated with substantial clinical benets
and has become the standard of practice in severe infections,
such as community-acquired and nosocomial pneumonia or
bacteraemia.
3638
From a public health perspective, limiting antibiotic use for
AOM would contribute to the battle against antimicrobial drug
resistance. This is important since it has been shown that resist-
ance rates of major respiratory pathogens isolated from children
attending day care centres are considerable.
39
At a patient level,
unnecessary use of antibiotics contributes to colonization with
resistant pathogens,
40
which may cause subsequent infections.
41
Resistant pathogens might also spread to close contacts of the
affected children.
42,43
The potential methodological limitations of our meta-analysis
should be taken into consideration in assessing its ndings. First,
similarly to many other studies of this type, appreciable hetero-
geneity exists regarding the inclusion diagnostic criteria, along
with the types of outcomes evaluated, and the methods and
timing of the assessment of the outcomes among the included
RCTs. It has been shown that such differences may appreciably
inuence ndings in studies of AOM.
44
Yet, we found no sig-
nicant difference between the ndings of trials using rigorous
diagnostic inclusion criteria and the remaining trials.
Variability was also observed regarding the antibiotic dosages
used in the included trials, raising concerns regarding the adequacy
of antibiotic dosing.
17,19
Additionally, the clinical course of AOM
was evaluated with the use of different methods such as question-
naires or diaries lled out by parents in four trials
14,15,18,22
and
over-the-phone diagnosis in one trial.
21
Moreover, in the watchful
waiting trials of AOM that were included in our meta-analysis,
their open-label or single-blinded design may have allowed bias to
interfere with the evaluation of the outcomes. This may be implied
by the fact that the effect of antibiotics in causing diarrhoea
appeared exacerbated compared with the subgroup analysis includ-
ing only placebo-controlled trials. Finally, it should be mentioned
that antibiotic resistance may be observed in a substantial pro-
portion of AOM cases in todays clinical setting,
45,46
thus compro-
mising the utility of antibiotics.
Furthermore, we did not perform an intention-to-treat analy-
sis, since such data were reported in only 5 of the 11 included
trials, with regard to the primary effectiveness outcome of our
meta-analysis.
14,15,17,22,24
In four of these ve trials, data on
the intention-to-treat population corresponded to those of the
clinically evaluable population that we included in our
meta-analysis.
15,17,22,24
In the remaining seven trials, the clini-
cally evaluable population constituted 84%96% of the
intention-to-treat population.
14,16,1821,23
Therefore, data on the
former type of population could be considered as a good
approximation of the missing data on the latter.
Pooling the placebo-controlled with the watchful waiting
trials may also raise some methodological concerns. We con-
sidered this combined analysis as a complementary one, mainly
contributing in the derivation of non-denitive conclusions
regarding secondary outcomes for which few of the trials
included in the meta-analysis reported specic data. Regarding
the primary effectiveness outcome that we selected for our
meta-analysis, namely clinical success, it was determined by
various criteria in the included RCTs and evaluated at different
time points. In addition, this outcome, although not as specic,
is more comprehensive compared with the evaluation of the
course of specic symptoms only, which was commonly per-
formed in prior meta-analyses in AOM. Specically, another
meta-analysis that used the severity and duration of pain as one
of the primary endpoints showed that antibiotic treatment
confers no benet over placebo in this regard within the rst
24 h, whereas it is associated with a small absolute reduction in
pain after the rst 2 days.
10
In our meta-analysis, we included trials that involved children
of various age groups. Yet, scarcity of data on the outcome of
children of different age strata precluded us from assessing the
utility of antibiotics over placebo or watchful waiting with
regard to this factor. It is well recognized, though, that children
younger than 2 years old, and particularly those younger than
6 months, are more prone to untoward events associated with
AOM.
47,48
Similarly, a recent meta-analysis concluded that anti-
biotic treatment is more benecial for children younger than
2 years old and for children with bilateral AOM.
49
Our meta-analysis, compared with recent ones,
10,49
has included
additional trials, which provides greater condence regarding the
variance of its ndings. Still, the main novelty of our meta-analysis
lies in the evaluation of the watchful waiting strategy in compari-
son with the immediate antibiotic treatment strategy.
In conclusion, our meta-analysis showed that antibiotics have
greater clinical effectiveness compared with placebo for the
treatment of AOM in children. This benet of antibiotics was
maintained when immediate antibiotic treatment was compared
with watchful waiting. The margin of benet conferred by anti-
biotic treatment does not appear to be large. Several other
factors, such as the rapidity of resolution of symptoms, along
with the frequency and nature of treatment-related adverse
events, the potential for occurrence of disease complications and
the community- and patient-related risks associated with anti-
microbial drug resistance development should be further con-
sidered in the evaluation of different therapeutic strategies for
AOM. Clinicians should bear in mind the above issues and also
consider patient-related factors, referring to disease severity and
the presence of adverse prognostic factors, in the relevant clini-
cal decision-making process.
Funding
None.
Transparency declarations
None to declare.
Supplementary data
Figure S1 and Tables S1 and S2 are available as Supplementary
data at JAC Online (http://jac.oxfordjournals.org/).
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